This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and Rationale Protein-protein interactions are central to many processes within cells and organisms, ranging from the assembly of the structural scaffold of cells to immune defense and cellular communication. How do biological molecules recognize their targets, and how do these interactions build up macromolecular complexes and networks responsible for biological regulation and complexity? The focus of this project is to develop and use computational protein design methods to understand and engineer protein-protein interactions. To develop the required predictive understanding of the physical basis of affinity and specificity in protein interfaces is a major challenge, but such a description would allow the design of new protein-protein interactions and would ultimately open the way to engineer new functions and modulate cellular behavior in a predictive manner.